NE Oncology Issue – June 2007

Lesley McKarney

First-line data for lapatinib in HER2-positive advanced breast cancer is encouraging


In tumours of 20% to 25% of women with breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is amplified, generating as many as 50 or 100 gene copies per cell.1 Overexpression of HER2 has been shown to be associated with a more aggressive disease with a poorer prognosis.1 Lapatinib has shown promising results in preclinical and early clinical studies as an orally active small molecule tyrosine kinase inhibitor that targets both HER2 and the epidermal growth factor receptor (EGFR or HER1).2 In patients with refractory disease, i.e., those who have received multiple prior chemotherapy regimens and trastuzumab, lapatinib given as a single agent results in response rates of 5% to 10%, as demonstrated in two separate trials. In patients who have not received prior treatment in the metastatic setting and who are trastuzumab-naïve, the response rate appears to be approximately 25%.2

The combination of lapatinib and capecitabine as a treatment for metastatic HER2-positive breast cancer in patients for whom other treatments have failed has received regulatory approval by the U.S. Food and Drug Administration. This follows the positive data from a pivotal open-label phase III trial in which the time to progression almost doubled in patients with HER2-positive advanced breast cancer treated with lapatinib in combination with capecitabine versus capecitabine alone.3 The combination of lapatinib and the cytotoxic capecitabine resulted in a 22% response rate, while the response to capecitabine alone was 14% (p = 0.09). Moreover, the time to disease progression was significantly better in the combination arm (8.4 months) compared with the single arm (4.4 months) (p <0.001, hazard ratio = 0.47).

In a current trial, the combination of a taxane with lapatinib in women with advanced breast cancer is being evaluated.4 At ASCO 2007, Angelo Di Leo and colleagues presented a planned subset analysis of HER2 subgroups of the phase III randomized, double-blind, placebo-controlled, multicentre trial evaluating efficacy and tolerability of lapatinib plus paclitaxel.

Study design

  • The trial enrolled 580 patients with incurable HER2-negative or unknown breast cancer in Stage III or IV, who had no prior treatment for metastatic disease.
  • Median age was 51 years in the paclitaxel plus lapatinib arm, and 52 years in the paclitaxel plus placebo arm; the majority of patients had Stage IV disease (87% and 86%, respectively).
  • Patients were randomly assigned to receive paclitaxel 175 mg/m2 every three weeks plus either lapatinib 1,500 mg daily by mouth (n = 293) or a placebo (n = 286). Two patients on the paclitaxel plus placebo arm received both paclitaxel and lapatinib.
  • The primary endpoint was time to progression; the study was designed with 90% power to detect 40% proportional increase in median time to progression of the intent-to-treat population.
  • Secondary endpoints included event-free survival (EFS), overall survival (OS), overall response rate (ORR), clinical benefit rate, ORR plus stable disease (SD) ≥6 months, duration of response, and safety.

Key findings

  • The addition of lapatinib to paclitaxel significantly improved response rates compared with paclitaxel alone in the entire study population (35% compared with 25%, respectively) (Table 1).
  • The median duration of response, overall survival, and event-free survival, however, was similar between the two treatment arms for the entire study population of HER2-negative or unknown breast cancers.
    • Ninety-one patients were retrospectively identified as having HER2-positive disease by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) analysis of tumour samples, 52 in the lapatinib-paclitaxel arm and 39 in the paclitaxel-placebo arm.
  • In the patients who were HER2-positive, the findings showed that 60% of patients who were administered lapatinib plus paclitaxel experienced a complete or partial response, compared to 36% on paclitaxel alone (Figure 1).
  • Moreover, in this sub-group, the median event-free survival was significantly longer for patients who received the lapatinib combination, at 7.9 months compared with 5.2 months in those who received paclitaxel alone, while time to progression was 8.1 months compared with 5.8, respectively (Table 2).


  • Patients who received the combination of lapatinib and paclitaxel had a higher incidence of diarrhea than those on paclitaxel alone, as well as a higher rate of nonprogression-related death (2.7% versus 0.6%) (Table 3).

Key conclusions

  • Lapatinib, in combination with paclitaxel, increased progression-free and event-free survival in the first-line treatment of patients with metastatic HER2-positive breast cancer, compared with paclitaxel alone in this relatively small subgroup of patients.
  • However, patients with metastatic HER2-negative breast cancer do not appear to derive additional benefit of lapatinib added to paclitaxel compared with paclitaxel alone.
  • The improvement in time to progression came at the expense of increased toxicity, particularly diarrhea, mucositis, and rash. The latter may be related to pharmacokinetic interactions between the drugs.
  • The authors suggest that results warrant further trials to assess the predefined molecular subtypes of breast cancer in larger randomized trials.

References: 1. Jørgensen JT, Vang Nielsen K, Ejlertsen B. Pharmacodiagnostics and targeted therapies — a rational approach for individualizing medical anticancer therapy in breast cancer. Oncologist 2007;12(4):397–405. 2. Nelson HM, Dolder CR. Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother 2006;40:261–269. 3. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355(26):2733–2743. 4. Di Leo A, Gomez H, Aziz Z, et al. Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients with metastatic breast cancer: a phase III randomized, double-blind study of 580 patients. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1–5, 2007; Chicago, Illinois: Abstract 1011.

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Vera Hirsh, MD, FRCPC
Chief of the Hematology-Oncology Service, Santa Cabrini Hospital
Associate Professor, Medicine and Oncology, McGill University
Associate Physician, Oncology Service, at the Royal Victoria, Montreal General, and Montreal Chest Hospitals
With a current practice in both hematology and oncology, Dr. Vera Hirsh is an associate professor of medicine and oncology at McGill University. Her research at the Quebec Pulmonary Unit focuses on the treatment of lung cancer, and she continues to chair ongoing international chemotherapy trials. Dr. Hirsh chaired the Quebec Lung Cancer Committee to establish guidelines for the treatment of lung cancer. In addition, she has published abstracts, articles, and book chapters. Dr. Hirsh is a member of advisory boards for many pharmaceutical companies and the Medical Oncology Standing Committee of RTOG.

Christine Cripps, MD, FRCPC
Medical Oncologist, Director,
Continuing Medical Education,
Ottawa Hospital Regional Cancer Centre
Dr. Christine Cripps is a medical oncologist and director of the Continuing Medical Education Department at the Ottawa Hospital Regional Cancer Centre. She also holds a position of Associate Professor, Medicine at the University of Ottawa. A keen teacher, Dr. Cripps’ main areas of interest include gastrointestinal cancer and head and neck cancer. She also enjoys cycling, skiing, and sailing when time permits.

Stephen K. L. Chia, MD, FRCPC
Assistant Professor of Medicine Department of Medicine
University of British Columbia
British Columbia Cancer Agency
Dr. Chia is a staff oncologist with the British Columbia Cancer Agency (BCCA), Vancouver, Canada. He also serves as physician coordinator for both the breast cancer and head and neck cancer clinical trials at the BCCA – Vancouver Cancer Centre. He is an active researcher in phase I-III trials in breast cancer, head and neck cancer and investigational new drugs. He is currently carrying out studies in breast cancer with grant funded research from the National Cancer Institute of Canada, Canadian Breast Cancer Alliance and Canadian Breast Cancer Foundation – British Columbia/Yukon Chapter. Dr. Chia is an active member of the British Columbia Breast Tumor Group, Breast Cancer Systemic Policy Group and Head and Neck Tumor Group.

José Chang, MD, FRCPC
Head of Medical Oncology, RS
McLaughlin Durham Regional Cancer Centre, Oshawa
Dr. José Chang is the principal investigator and site representative for the National Cancer Institute of Canada Clinical Trials Group, and is an examiner for the Medical Council of Canada. His research interests lie in the areas of breast cancer, melanoma, lymphoma, and quality of life during chemotherapy. Dr Chang has presented at major oncology meetings of the American Society of Clinical Oncology, San Antonio Breast Cancer Symposia, and European Breast Cancer Conference. A member of the editorial board of the journal Current Oncology, Dr. Chang has published in journals such as the Journal of Clinical Oncology, European Journal of Cancer, and Canadian Medical Association Journal.